Poly(ADP-ribose) synthetase is a chromatin bound enzyme that adds chains of ADP-ribose in tandem to nuclear proteins. This enzyme is activated by DNA damaging agents such as gamma, x-ray and u.v. irradiation and by DNA alkylating agents. We have synthesized and tested 6 compounds which are inhibitors of the synthetase and found that the ability of 4 of 6 of them to block DNA repair is directly correlated with the compound's potency as a synthetase inhibitor. The compounds ranked in order of their ability to block DNA repair are 3-acetlaminobenzamide greater than 3-hydroxybenzamide=benzamide >>3-aminobenzamide. 3-nitrobenamide, was found to be much more inhibitory for the repair of DNA chain breaks than was expected based on its potency as a poly(ADP-ribose) synthetase inhibitor. This compound appears to block DNA repair indirectly via its potency as an RNA synthesis inhibitor. Indeed, all of the benzamides were found to block RNA synthesis to some extent but this characteristic was not related to the potency of the compound as a synthetase inhibitor. Activity of the benzamides to block RNA synthesis was linearly related to the electron withdrawing potency of the substituent group at the 3 position of the benzamide ring-i.e., to the Hammet's constant. 3-methoxybenzamide was found to be a potent synthetase inhibitor but was a relatively poor inhibitor of DNA repair. Differences in benzamide analog effects on DNA repair may be partly a consequence of differences in analog uptake. They are probably not due to pertubation of nucleotide triphosphate pools in the cells since the most potent synthetase inhibitor, 3-acetylaminobenzamide at very high concentrations had no effect on the nucleotide triphosphate level in cells. Whether or not the benzamides block DNA repair via their inhibition of poly (ADP-ribose) synthetase is not clear. However, the compounds may be clinically useful since they potentiate the cell killing effects of chemotheraputic agents such as bleomycin, adriamycin, NMU and methylmethane sulfonate, agents that cause DNA damage.